Human breast tumors override the antiangiogenic effect of stromal thrombospondin‐1 in vivo

The antiangiogenic extracellular matrix protein thrombospondin‐1 (TSP‐1) inhibits tumor growth and metastasis in animals. However, the clinical relevance of such findings are equivocal as increased stromal TSP‐1 expression has been associated with either good or poor prognosis. In an effort to obtain a more integrated understanding of the role of TSP‐1 in breast cancer, we first used a breast tumorigenesis model in which tumor‐associated stromal fibroblasts were engineered to produce high levels of TSP‐1. We demonstrate here that stromal TSP‐1 delayed human MDA‐MB‐231/B02 breast tumor growth. However, this delay in MDA‐MB‐231/B02 tumor growth upon exposure to TSP‐1 was associated with an increased vascular endothelial growth factor (VEGF) expression in tumor cells themselves, leading to a tumor growth rate comparable to that of tumors whose fibroblasts did not overproduce TSP‐1. Clinical evidence also suggested that primary breast carcinomas have adapted to escape the effects of stromal TSP‐1. TSP‐1 was found to be expressed in the stroma of human breast carcinomas where, although its level correlated with decreased vascularization, it was unexpectedly associated with a reduction of relapse‐free survival. In metastatic axillary lymph nodes, tumor cells expressed high levels of VEGF and TSP‐1 expression were no longer associated with a decreased vascularization. Overall, these results suggest that a resistance may develop early in human breast cancers as a result of high in situ exposure to stromal TSP‐1, leading to disease progression. © 2005 Wiley‐Liss, Inc.